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Acute lung injury

ARDS / DAD


Akira Yoshikawa, M.D.
Andrey Bychkov, M.D., Ph.D.

Last author update: 26 August 2022
Last staff update: 29 November 2022

Copyright: 2003-2025, PathologyOutlines.com, Inc.

PubMed search: (Acute respiratory distress syndrome) ARDS (Diffuse alveolar damage) DAD

See also: Acute fibrinous and organizing pneumonia

Akira Yoshikawa, M.D.
Andrey Bychkov, M.D., Ph.D.
Page views in 2024: 22,738
Page views in 2025 to date: 11,396
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Diagrams / tables | Clinical features | Diagnosis | Laboratory | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Virtual slides | Cytology description | Positive stains | Electron microscopy description | Videos | Sample pathology report | Differential diagnosis | Additional references | Practice question #1 | Practice answer #1 | Practice question #2 | Practice answer #2
Cite this page: Yoshikawa A, Bychkov A. ARDS / DAD. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lungnontumordiffusealveolardamage.html. Accessed July 16th, 2025.
Definition / general
  • In 1994, the American European Consensus Conference (AECC) defined acute respiratory distress syndrome (ARDS) as the acute onset of hypoxemia with bilateral infiltrates on frontal chest radiograph, with no evidence of left atrial hypertension (Am J Respir Crit Care Med 1994;149:818)
  • In 2012, the ARDS Task Force revised the new definition (see Diagnosis) (JAMA 2012;307:2526)
  • Diffuse alveolar damage (DAD) is manifested by injury to alveolar lining and endothelial cells, pulmonary edema, hyaline membrane formation and later by proliferative changes involving alveolar and bronchiolar lining cells and interstitial cells (Am J Pathol 1976;85:209)
Essential features
  • Acute and rapidly progressive hypoxia with bilateral pulmonary edema due to alveolar injury caused by pulmonary or systemic insults
  • 40% die within 28 days from onset of ARDS, mainly due to infection / sepsis and multiple organ dysfunction syndrome
  • Although DAD is the typical morphology of ARDS, clinical syndrome of ARDS is not synonymous with the pathologic diagnosis of DAD
  • DAD pattern is often characterized by hyaline membranes in acute phase but shows a wide variety of findings that makes the diagnosis challenging
Terminology
  • Previously known as adult respiratory distress syndrome
  • Acute lung injury, an overlapping entity suggested in AECC definition, was removed from Berlin definition; the AECC definition of acute lung injury non-ARDS is compatible with Berlin definition of mild ARDS (JAMA 2012;307:2526)
ICD coding
  • ICD-10: J80 - acute respiratory distress syndrome
Epidemiology
  • Mean age: 60 years old; from children to elderly
  • M:F = 3:2
  • Incidence of 10.6 - 78.9 per 100,000 person years (N Engl J Med 2005;353:1685, Intensive Care Med 2009;35:1352)
  • Incidence of ARDS in intensive care unit (ICU) (JAMA 2016;315:788):
    • 10.4% of all ICU patients
    • 67.2% of patients with acute hypoxemic respiratory failure
    • ARDS is frequently undiagnosed (60.2% recognized by clinician) or late diagnosed (34.0% recognized at the time of criteria fulfillment)
Sites
  • Diffusely involves bilateral lobes of the lung without upper or lower lobe predominance
  • Distribution can be regional, depending on the degree and cause of the inflammation
Pathophysiology
  • Pathogenesis (N Engl J Med 2000;342:1334, Lancet 2016;388:2416)
    • Exudative (acute) phase: 1 - 7 days
      • Neutrophil mediated inflammation destroys the alveolar capillary barrier (alveolar epithelium and endothelium), increases its permeability and causes intra-alveolar hemorrhage and edema
      • Protein rich edema interacts with alveolar surfactants, resulting in decreased pulmonary compliance
      • Hyaline membranes develop on alveolar wall where epithelium is denudated and disrupted
    • Proliferative / organizing (subacute) phase: 1 - 3 weeks
      • Proliferation of type II pneumocytes and subsequent differentiation into type I pneumocytes
      • Proliferation of myofibroblasts
      • Drainage of alveolar edema by restored type II pneumocytes
    • Fibrotic (chronic) phase: after 3 weeks
      • Collagenous fibrosis in alveolar spaces and interstitium
      • Refractory rigidity of alveoli due to architectural remodeling
  • Pathophysiology of hypoxia
    • Collapse of alveoli
    • Increased right to left intrapulmonary shunt
    • Decreased pulmonary compliance
      • Surfactant malfunction
      • Fibrosis
    • Decreased diffusing capacity due to pulmonary edema
    • Increased ventilation perfusion mismatch
    • Increased pulmonary vascular resistance
  • Mechanism of ARDS to cause multiple organ dysfunction syndrome is not clear
Etiology

Direct lung injury Indirect lung injury
  • Common causes
    • Infectious pneumonia
    • Aspiration of gastric contents
  • Common causes
    • Sepsis
    • Severe trauma or burn, especially
        with shock and multiple transfusions
  • Less common causes
    • Pulmonary contusion
    • Fat emboli
    • Near drowning
    • Inhalational injury (particle, gas)
    • Reperfusion pulmonary edema after
        lung transplantation or pulmonary embolectomy
  • Less common causes
    • Cardiopulmonary bypass
    • Drug
    • Acute pancreatitis
    • Autoimmune disease
    • Transfusion related acute lung injury
Diagrams / tables

Images hosted on other servers:
Acute phase

Acute phase

Organizing phase

Organizing phase

Clinical features
  • Acute and progressive respiratory failure
    • Usually starts 12 - 48 hours after the initial insult
    • Shortness of breath; dyspnea on exertion followed by dyspnea at rest
    • Hypoxia; PaO2 / FiO2 ≤ 300 mm Hg
  • Often followed by sepsis and multiple organ dysfunction syndrome (JAMA 2016;315:788)
  • Respiratory dysfunction and physical disability may persist for months after remission of ARDS, with gradual improvement (N Engl J Med 2003;348:683)
Diagnosis
  • Diagnosis of ARDS is based on clinical manifestation and its severity is evaluated with ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2 / FiO2)
  • Berlin definition (JAMA 2012;307:2526)
    • Timing
      • Within 1 week of a known clinical insult or new or worsening respiratory symptoms
    • Chest imaging
      • Assessed by chest Xray or CT
      • Bilateral opacities; not fully explained by effusions, lobar / lung collapse or nodules
    • Origin of edema
      • Respiratory failure not fully explained by cardiac failure or fluid overload
      • Need objective assessment (e.g. echocardiography) to exclude hydrostatic edema if no risk factor present
    • Oxygenation (with positive end expiratory pressure [PEEP] or continuous positive airway pressure [CPAP] ≥ 5 cm H2O)
      • Mild: 200 < PaO2 / FiO2 ≤ 300 mm Hg
      • Moderate: 100 < PaO2 / FIO2 ≤ 200 mm Hg
      • Severe: PaO2 / FiO2 ≤ 100 mm Hg
  • Not all ARDS show DAD pattern
    • ARDS can present with organizing DAD and acute fibrinous organizing pneumonia as well
    • DAD can be seen as a nonspecific manifestation of the agonal phase and shock
  • Although rarely performed, lung biopsy can be helpful for critical care and prognosis estimation in patients with ARDS
Laboratory
  • Arterial blood gas test
    • Hypoxemia
    • Ratio of pulse oximetric oxygen saturation to FIO2 (SpO2 / FiO2) may be helpful for instant follow up (Chest 2007;132:410)
      • SpO2 / FiO2 of 235 ≈ PaO2 / FiO2 of 200 (sensitivity: 85%, specificity: 85%)
      • SpO2 / FiO2 of 315 ≈ PaO2 / FiO2 of 300 (sensitivity: 91%, specificity: 56%)
  • Other blood tests
    • Increased C reactive protein
    • Increased procalcitonin in septic ARDS
    • Increased ferritin (Am J Respir Crit Care Med 1999;159:1506)
    • Increased KL-6
    • Brain natriuretic peptide (BNP) test may helpful to distinguish ARDS and cardiogenic pulmonary edema (Chest 2007;131:964)
      • BNP ≤ 200 pg/mL is suggestive for ARDS (sensitivity: 40%, specificity: 91%)
      • BNP ≥ 1,200 pg/mL is suggestive for cardiogenic pulmonary edema (sensitivity: 52%, specificity: 92%)
Radiology description
  • General
    • Heterogeneous bilateral shadows due to pulmonary edema
    • Rule out atelectasis, pleural effusion and mass
    • Takes 12 - 24 hours from onset to be apparent
  • Chest Xray
    • Exudative phase: ground glass opacity and consolidation with air bronchogram
    • Proliferative / organizing and fibrotic phases: reticular shadow and volume reduction
  • Chest CT (Radiology 1999;211:859)
    • Exudative phase
      • Patchy to diffuse ground glass opacity, with or without interlobular septal thickening
      • Dorsal consolidation due to infiltrate
    • Proliferative / organizing phase
      • Ground glass opacity with bronchiolectasis and bronchiectasis
      • Volume reduction
    • Fibrotic phase
      • Septal thickening and reticular shadow in ground glass opacity
      • Peripheral cystic and honeycomb-like lesions due to fibrosis
Radiology images

Images hosted on other servers:
Changes in ARDS

Changes in ARDS

Exudative phase   Exudative phase

Exudative phase

Exudative phase   Exudative phase

Exudative phase

Exudative phase

Exudative phase


Proliferative / organizing phase   Proliferative / organizing phase

Proliferative / organizing phase

Fibrotic phase

Fibrotic phase

ARDS on CT

ARDS on CT

ARDS on CT

ARDS on CT

ARDS on CT

ARDS on CT

Prognostic factors
Case reports
Treatment
  • Removal of the original insult
  • Oxygen therapy for respiratory failure (Lancet 2016;388:2416)
    • Mechanical ventilation
      • PEEP or CPAP ≥ 5 cm H2O
      • With or without neuromuscular blockade, prone position and extracorporeal membrane oxygenation
  • Other supportive care
    • Fluid management
    • Pharmacotherapy
      • Glucocorticoid
      • Anticoagulant
  • Since no treatment drastically improves the respiratory failure of ARDS, respiratory and systemic supportive care is needed until the patient survives from ARDS
Gross description
  • Brown to gray consolidative lesion with indistinct borders, diffusely involving bilateral lobes
  • Elastic hard and greasy due to transudate within alveolar spaces and interstitial edema
  • Heavy and shrunken due to fibrosis and collapse of the tissue
  • Dots of hemorrhage on pleural surface
Gross images

Contributed by Yale Rosen, M.D.
Diffuse alveolar damage (DAD)   Diffuse alveolar damage (DAD)   Diffuse alveolar damage (DAD)

Diffuse alveolar damage (DAD)

Patchy lung involvement

Patchy lung involvement


Diffuse alveolar damage (DAD)   Diffuse alveolar damage (DAD)   Diffuse alveolar damage (DAD)

Diffuse alveolar damage (DAD)

Microscopic (histologic) description
  • Histopathology of DAD progresses from exudative (acute) phase through proliferative / organizing (subacute) phase to chronic fibrotic phase roughly corresponding to the period of ARDS (Am J Pathol 1976;85:209, Arch Pathol Lab Med 2010;134:719, Clin Chest Med 2000;21:435, N Engl J Med 2000;342:1334)
    • Phase of the disease is almost synchronous throughout the lung
    • Features of different phases may be combined in the transitional period or with repeated bouts of lung injury
  • Exudative (acute) phase
    • Alveolar change
      • Hyaline membranes on alveolar duct or sacs
      • Interstitial and intra-alveolar edema
      • Collapsed alveoli
    • Epithelial change
      • Denudation and necrosis of type I pneumocytes
    • Vascular change
      • Necrosis of endothelial cells
      • Neutrophil aggregation
      • Microthromboemboli
      • Hemorrhage
  • Proliferative / organizing (subacute) phase
    • Alveolar change
      • Remnants of hyaline membrane with or without organization
      • Interstitial and intra-alveolar proliferation of myofibroblasts
      • Lymphocytic infiltration
    • Epithelial change
      • Proliferation / hyperplasia of type II pneumocytes
    • Vascular change
      • Endothelial injury and thromboemboli in arterioles
  • Fibrosis phase
    • Alveolar change
      • Collagenous fibrosis
      • Microscopic honeycomb-like change
      • Traction bronchiolectasis
    • Epithelial change
      • Squamous metaplasia / hyperplasia
    • Vascular change
      • Remodeling of arteries
      • Intimal fibrosis
      • Thickening of media
  • Others
    • May have superimposed pneumonia
    • Fibrin deposition
    • DAD with prominent organizing pneumonia is also called organizing DAD
Microscopic (histologic) images

Contributed by Akira Yoshikawa, M.D. and Yale Rosen, M.D.
Hyaline membrane   Hyaline membrane

Hyaline membrane

Hyaline membrane   Hyaline membrane

Hyaline membrane

Hyaline membrane

Hyaline membrane

Hyaline membranes and fibrin

Hyaline membranes and fibrin



Masson body

Masson body

Masson body

Masson body

Masson body

Masson body

Organizing DAD

Organizing DAD

Collagenous fibrosis

Collagenous fibrosis



Fibroblastic proliferation   Fibroblastic proliferation

Fibroblastic proliferation

Fibroblastic proliferation   Fibroblastic proliferation

Fibroblastic proliferation

Interstitial organization

Interstitial organization

Inflammatory cells

Inflammatory cells

Virtual slides

Images hosted on other servers:

Exudative phase

Cytology description
  • Bronchoalveolar lavage (BAL) fluid
    • Increased neutrophils in ARDS
    • Can be helpful for the diagnosis of underlying disease
Positive stains
  • Fiber staining (e.g. elastica van Gieson) is helpful to evaluate fibrosis and to evaluate the destruction of the alveolar architecture
  • Giemsa, Grocott and Ziehl-Neelsen stains are helpful to identify pathogens
  • Immunohistochemistry (not of practical utility):
    • Cytokeratin highlights collapsed alveoli and lung architecture
Electron microscopy description
  • Changes in epithelium, endothelium and interstitium (N Engl J Med 2000;342:1334)
    • Exudative phase
      • Vacuolization in damaged endothelial cells
      • Replacement of epithelial cells by hyaline membrane on the basement membrane
    • Proliferative / organizing and fibrotic phases
      • Reepithelialization of type II pneumocytes with microvilli and lamellar bodies with surfactant
      • Flattening of cytoplasm and loss of lamellar bodies and microvilli of type II pneumocyte, indicating transformation to type I pneumocyte
      • Collagen deposition
Videos
 

Histology of DAD

Sample pathology report
  • Lung, autopsy:
    • Diffuse alveolar damage (see comment)
    • Comment: Histologic sections reveal diffuse alveolar damage in subacute and chronic phases involving bilateral lobes; the former is represented by fibrin deposition, organizing pneumonia and focal hyaline membranes and the latter by interstitial fibrosis, fibroblastic foci and the destruction of alveolar architecture. Acute bacterial pneumonia is also superimposed.
Differential diagnosis
  • Major entities:
  • Minor entities:
    • Organizing pneumonia:
      • Migratory sign on imaging
      • Good response to corticosteroid
    • Eosinophilic pneumonitis:
      • Current smoker or history of particle inhalation
      • Eosinophilia (> 25%) in bronchoalveolar lavage
      • Good response to corticosteroid
    • Hypersensitivity pneumonitis:
      • History of antigen exposure
      • Remission of symptoms after removal of the causative antigen
      • Lymphocytosis (> 30%) in bronchoalveolar lavage
      • Diffuse centrilobular nodular shadow with ground glass opacity, usually in upper lobes
    • Miliary tuberculosis:
      • Diffuse nodular shadow (≤ 3 mm) involving whole lobes
      • Mycobacterium tuberculosis in bronchoalveolar lavage or biopsy specimen
    • Lymphangitic carcinomatosis:
      • Known malignancy
      • Tumor cells in bronchoalveolar lavage or biopsy specimen
Practice question #1


Which phase of diffuse alveolar damage (DAD) is most clearly demonstrated in this histological image?

  1. Active
  2. Exudative (acute)
  3. Fibrotic (chronic)
  4. Postinflammatory
  5. Proliferative / organizing (subacute)
Practice answer #1
E. Proliferative / organizing (subacute). Masson body, polypoid proliferation of spindle shaped fibroblasts, is noted in the alveoli.

Comment Here

Reference: ARDS / DAD
Practice question #2
Which of the following findings is most suggestive of acute respiratory distress syndrome (ARDS) / diffuse alveolar damage (DAD)?

  1. Bacterial pneumonia
  2. Diffuse collagenous fibrosis
  3. Hyaline membranes
  4. Organizing pneumonia
  5. Proliferation of atypical pneumocytes
Practice answer #2
C. Hyaline membranes. Hyaline membranes morphologically represent the damage of pneumocytes and endothelium in DAD.

Comment Here

Reference: ARDS / DAD
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